Monocytes and macrophages fundamentally originating from the bone marrow and spleen - pro-inflammatory Ly6Chi monocytes in mice (CD14hi cells in humans) and C-C chemokine receptor 2 (CCR2)+ monocyte-derived macrophages (MDMs) - contribute importantly to tissue injury and left ventricular (LV) remodeling in chronic heart failure (HF), suggesting that these cells may represent therapeutic targets for immunomodulation. Importantly, monocytes and MDMs exhibit circadian variation in multiple functional parameters, in large part due to a robust cell-autonomous molecular clock, which is regulated by the CLOCK/BMAL1 transcriptional complex and subject to an autoregulatory loop involving Rev-erba. Notably, whether the intrinsic circadian clock in monocytes and MDMs is disrupted in HF and its mechanistic link to inflammation and disease progression is entirely unknown. Our pilot studies suggest that monocyte and MDM clock disruption is characteristic of HF, and that monocyte/macrophage Bmal1 (and subsequent Rev-erba/b) loss is associated with upregulation of the immune activator E4bp4, and aggravation of LV remodeling. Based on these data, we hypothesize that the monocyte/MDM clock is dysfunctional in HF, leading to pathological inflammation and cardiac remodeling in a REV-ERBa-linked and E4BP4-dependent manner, and that clock correction is a key molecular target for immunomodulation. Three Aims will test this hypothesis. In Aim 1, we will define alterations in the monocyte circadian clock in HF using a murine coronary ligation model, and test whether monocyte/macrophage clock disruption in myeloid-specific Bmal1 knockout (MBK) mice exacerbates inflammation, innate immune expansion, and LV remodeling during HF. We will also measure inflammatory and clock genes in CD14hi monocytes from humans with HF. In Aim 2, we will delineate the role of monocyte-localized E4bp4, a clock-controlled inflammatory transcription factor and direct target of Rev-erba, in HF by assessing inflammation and LV remodeling after coronary ligation in myeloid-specific E4bp4 knockout (MEK) mice. We will also evaluate whether monocyte E4BP4 suppression rescues the aggravated LV remodeling observed with monocyte/macrophage clock disruption by inducing HF in myeloid-specific Bmal1/E4bp4 double knockout mice. In Aim 3, we will mechanistically establish the potential of targeting the circadian clock as a therapeutic approach in HF, by testing whether treatment with SR9009, a synthetic REV-ERBa/b agonist, favorably modulates monocytes and MDMs and ameliorates or reverses LV remodeling in wild-type mice with established HF, and then in MEK HF mice to determine whether the effects of SR9009 require monocyte/macrophage E4bp4. We will also evaluate the ex vivo activation responses of human HF CD14hi monocytes to the agonist. These studies will further our understanding of how changes in the macrophage circadian clock modulate both inflammation and disease progression in HF, and test novel approaches to immunomodulation using genetic and pharmacological strategies to correct the pathological changes induced by clock disruption.